1. Field of the Invention
This invention relates to the control of the inflammatory response, to pharmaceuticals that inhibit or decrease inflammation, to pharmaceuticals that promote, induce or increase inflammation and to treatment of disease states by inhibiting or promoting inflammation. In particular, this invention relates to control of the activity or the amount or both the activity and the amount of heme-oxygenase in the body.
This invention finds in addition to other applications, particular application in the treatment of diseases manifested in or exacerbated by an inflammatory response (such as in the treatment of chronic inflammatory diseases, for example, rheumatoid arthritis), in humans suffering hypersensitivity reactions such as in asthma, in humans suffering conditions in which ROS (Reactive Oxygen Species) have a pathogenic role such as reperfusion injury and atherosclerosis and, in humans having immunosuppressed states resulting from drug treatments or from pathologies such as AIDS.
2. Related Art
Chronic inflammatory diseases place a heavy social and economic burden on the resources of many nations, but the number of safe and effective treatments is limited. To date, the major research effort has concentrated on those mediators responsible for the initiation and maintenance of the pathological process. In contrast little attention has been focused on endogenous factors responsible for the resolution of the inflammation.
The main anti-inflammatory pharmaceutical agents are the glucocorticoids and the non-steroidal anti-inflammatory drugs (NSAIDs). Both suffer from well catalogued disadvantages, indeed nearly one quarter of adverse drug reactions reported in the UK are due to NSAIDs. Side-effects of NSAIDs commonly affect the gastrointestinal tract, and also the liver, kidney, spleen, blood and bone marrow. NSAIDs are not effective in treatment of some chronic inflammatory disorders.
Glucocorticoids are powerful anti-inflammatory agents, suppressing both acute and chronic phases of inflammation. They carry the hazard, however, that they also suppress the immune response and can decrease many aspects of essential cell repair processes. Generally, they must be given by injection and are not effective on oral administration.
There thus exists an on-going need for further anti-inflammatory drugs, which can be given orally and which are effective against chronic inflammation.
Conversely, a number of diseases are known in which there is a significant suppression of the inflammatory response. One example is acquired immune deficiency syndrome (AIDS) in which infection by HIV leads typically to such immuno-suppression that an infected person dies from a separate, opportunistic, infection, often a bacterial or viral infection rarely fatal in a healthy person. Stimulation or induction of inflammation in this case could assist in preventing death from non-HIV infections. However, no suitable pharmaceutical is known for this pro-inflammatory purpose.
Heme (ferri-protoporphyrin-IX) plays a vital role in cellular metabolism, functioning as the prosthetic group of hemeproteins (e.g., hemoglobin and cytochromes). It's catabolism is a two-step process. The first, and rate limiting reaction, is the production of biliverdin and carbon monoxide by the microsomal enzyme heme-oxygenase. The second step is the production of bilirubin from biliverdin by the cytosolic enzyme, biliverdin reductase.
Heme-oxygenase is found in liver, kidney, spleen and skin, and has also been localized to specific cell types, notably fibroblasts and macrophages. The enzyme exists in at least two isoforms, one constitutive and the other inducible. Heme, heavy metal ions (e.g., tin, gold, platinum and mercury) and transition metal ions (e.g., iron, cobalt, chromium and nickel) can all induce heme-oxygenase. In addition, heme-oxygenase is induced as part of a generalized stress response to stimuli such as thermal shock (hence the alternative name heat-shock protein 32; hsp32), oxidative stress and cytokines such as interleukin-1 (IL-1), tumor necrosis factor and IL-6. The stress response is seen as beneficial in that it results in protection of vulnerable cell enzymes from inactivation.
Animal biles have been used in traditional Chinese medicine for centuries in the treatment of bronchitis, asthma and other hypersensitivity reactions. More recently, it has been shown that biliverdin and bilirubin scavenge reactive oxygen species (ROS) which can have a range of proinflammatory effects including inactivation of protease inhibitors, depolymerization of hyaluronic acid to angiogenic fragments and alteration of proteins to give rise to endogenous antigens.
Heat shock proteins (HSPs) or stress proteins are a group of proteins that are among the most highly conserved and abundant proteins in the biosphere. Although many of the isoforms of the proteins are expressed under normal physiological conditions and serve vital roles in the cell, they are greatly upregulated by factors which threaten the integrity of the cell. These factors include heat and cold shock, oxygen radicals, heavy metals, hypoxia, infection, ethanol, ionophores and thiol reactive agents. This increase in the cell's concentration of HSPs leads to the cell being transiently resistant to an otherwise lethal insult, and unresponsive to some biological mediators.
The role of HSPs in pathological conditions has attracted much attention. Immune responses to HSPs can be highly cross-reactive and even auto-reactive due to their extensive inter-species amino acid homology. Immune responses to HSPs have already been implicated in adjuvant arthritis in the rat, pristane arthritis in the mouse, diabetes mellitus in the non-obese diabetic mouse, rheumatoid arthritis, systemic lupus erythematosus, atherosclerosis and in tumor surveillance. Therefore, it appears that HSPs may have a paradoxical effect in pathological conditions, having a cyto-protective effect on cells and tissue in stressful environments, but eliciting a detrimental immune response in some autoimmune diseases.
Nitric oxide (NO), formed from L-arginine and molecular oxygen by isoforms of the enzyme nitric oxide synthase (NOS EC 1.14.13.39), is involved in a variety of physiological and pathophysiological processes. The reactivity of this molecule and its capacity to complex with metalloproteins, underlies many of its biological actions. For example, activation by NO of heme-containing soluble guanylate cyclase (EC 4.6.1.2) in vascular smooth muscle results in vasoregulation, whilst in host defence, inhibition of iron-sulphur enzymes causes metabolic dysfunction in invading pathogens.
Inflammation involves the sequential release of various mediators including vasoactive mediators, chemoattractants, cytokines, prostaglandins, free radicals and proteases. In rheumatoid arthritis, a chronic inflammatory disease, HSPs are upregulated in the synovial lining of patients. However, their role in inflammation has yet to be completely elucidated.
Abraham et al., Int. J. Biochem. 20(6): 543-558 (1988) provides a general review of heme-oxygenase and its role in mammalian physiology including regulation of its activity by endogenous and exogenous factors. The interaction of this enzyme with NADPH-cytochrome P450 reductase is discussed, as is the role of heavy metal ions in inducing heme-oxygenase activity. Metal Porphyrins are taught as inhibitors. At p. 548 of the reference, the author states:
In general, heme-oxygenase activity increases when cells are under stress or in a disease state. In fact, the enzyme may be regarded as a red light signaling the occurrence of abnormality. PA1 In mammals and other vertebrates heme is oxidatively degraded by heme-oxygenase to form the open chain tetrapyrrole biliverdin. In mammals biliverdin is reduced to bilirubin by biliverdin reductase. In liver bilirubin is converted to the mono- and di- glucuronide conjugates by the hepatic glucuronyl transferase system prior to its excretion. PA1 Bilirubin is a toxic compound, but normally this toxicity is not manifest since bilirubin is rapidly bound to plasma proteins, transported to liver, conjugated and excreted. However, in the newborn, high undesirable concentrations of bilirubin exist in serum and may produce neurotoxicity. The intractable neurological syndrome known as "kernicterus" is the most severe manifestation of bilirubin toxicity. PA1 It has now been discovered that the compound Sn(tin)-mesoporphyrin (SnMP) can be employed in the treatment of mammals including humans in need of such treatment to decrease the rate of heme metabolism, to increase the rate at which heme is excreted and to control the rate of tryptophan metabolism in the liver.
Sacerdoti et al., Science 243:388-390 (1-20-89) asserts that hypertension was linked to kidney cytochrome P450 levels, and that enzyme could be depleted by inducing heme-oxygenase production. This was done by treatment with Co.sup.2+.
McCarty (Chemical Abstract, 100:1864024 (1984)) purports to teach the effect of selenium in reducing leukotrienes which are alleged to be prominent mediators of hyper-sensitivity and inflammation. McCarty, in fact, teaches the administration of a dietary adjuvant per os.
U.S. Pat. No. 5,102,670 relates to the reduction of ocular swelling by administering a heme-oxygenase inducer to the swollen eye of an individual to increase production of heme-oxygenase to reduce the amount of 12(R) hydroxyeicostetraenoic acid (12(R)-HETE) present in the eye as well as 12(R) Dihydroxyeicosatrienoic acid (12(R)-DIHETE) also present in the eye. The scheme presented in the patent for reducing corneoconjunctival swelling is thus dependent on the reduction of the arachidonic acid metabolites 12(R)HETE and 12(R)DIHETE found mainly in the eye. In particular, it is explained that the therapeutic effect is primarily on maintaining the blood--aqueous barrier, a barrier not seen other than in the eye. Thus, the teachings in the patent relate solely to the eye and have very little other applicability.
During about the same time period Messrs. George S. Drummond and Hallah Kappas of The Rockefeller University, Drummond, N.Y. were involved together and with others in research relating to heme-oxygenase. The result of the research appears embodied, at least in part, in U.S. Pat. Nos. 4,657,902; 4,699,903; 4,684,637; 5,010,073 and 5,223,494.
U.S. Pat. No. 4,657,902 purports to teach the use of the novel compound tin mesoporphyrin and compositions containing it to inhibit heme metabolism in mammals, to control the rate of tryptophan metabolism in mammals, and to increase the rate at which heme is excreted by mammals.
The patent disclosure provides as follows at Column 1, lines 22-36:
The inventors, therefore, provide at column 3, lines 43-48:
U.S. Pat. No. 4,699,903 purports to teach a method of increasing the rate at which heme is excreted by a mammal in need of increased disposal of heme by administering tin diiododeuteroporphyrin.
U.S. Pat. No. 4,684,637 discloses methods for decreasing the rate of metabolism for decreasing the rate of metabolism of heme in mammals by administration of tin or chromium protoporphrins IX.
U.S. Pat. No. 5,010,073 purports to relate to liposomal metalloporphyrin preparations for targeting the spleen for inhibition of heme-oxygenase activity in the spleen.
U.S. Pat. No. 5,223,494 purports to teach a method for inhibiting heme-oxygenase activity in the intestine by administering mesoporphyrin for reducing the absorption of iron from foodstuffs by animals in need of such prevention.
This latter group of patents relates to inhibiting heme-oxygenase in selected body tissues by targeting those body tissues (for example, the spleen or intestine) for specified purposes.